Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus

• Type of Material: Article
• Authors: Avanti Gokhale, Emory University; Chelsea E. Lee, Emory University; Stephanie Zlatic, Emory University; Amanda Freeman, Emory University; Nicole Shearing, Emory University; Cortnie Hartwig, Emory University; Oluwaseun Ogunbona, Emory University; Julia L. Bassell, Emory University; Meghan E. Wynne, Emory University; Erica Werner, Emory University; Chongchong Xu, Emory University; Zhexing Wen, Emory University; Duong Duc, Emory University; Nicholas Seyfried, Emory University; Carrie E. Bearden, University of California Los Angeles; Viktor Olah, Emory University; Matt Rowan, Emory University; Jill R. Glausier, University of Pittsburgh; David A. Lewis, University of Pittsburgh; Victor Faundez, Emory University
• Language: English
• Date: 2021-08-04
• Publisher: Society of Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2021 the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.2197-20.2021
• Title of Journal or Parent Work: Journal of Neuroscience
• Volume: 41
• Issue: 31
• Start Page: 6596
• End Page: 6616
• Grant/Funding Information: M.E.W. was supported by National Institutes of Health Grants F31AG067623 and 5T32NS007480.; This work was supported by National Institutes of Health Grant 1RF1AG060285 to V.F., Emory Catalyst Grant, Accelerating Medicine Partnership AD Grant U01AG061357, and National Institute on Aging Grant RF1AG053960.
• Keywords: Quality control; protein synthesis; mitochondria; Schizophrenia; Neurosciences & Neurology; CNV; schizophrenia; Science & Technology; Tetracycline antibiotics; Fragile X syndrome; Transcriptome alterations; Deletion syndrom; synapse; Protein synthesis; Neurosciences; Drosophilia; 2; Complex; Copy number; 22q11; Life Sciences & Biomedicine; neurodevelopmental
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Chemistry, Biochemistry; Biology, Cell

Abstract

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.